MANAGEMENT OF HOSPITAL-ACQUIRED FUNGAL INFECTIONS

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1 MANAGEMENT OF HOSPITAL-ACQUIRED FUNGAL INFECTIONS Paul D. Holtom, MD Associate Professor of Medicine and Orthopaedics USC Keck School of Medicine Numbers of Cases of Sepsis in the United States, According to the Causative Organism, Martin, G. S. et al. N Engl J Med 2003;348: Pathogens Causing Nosocomial Fungal Infections NNIS Hospitals % 1.3% 7.3% 78.3% Aspergillus Candida spp. C. glabrata All other spp. Beck-Sague,C, Jarvis, WR. Jour Inf Dis 1993; Vol 167: p

2 CANDIDA Most common fungal infection >100 species described Yeast-like organism that forms hyphae and pseudo-hyphae Wide range of clinical syndromes CANDIDEMIA Species C. albicans C. glabrata C. tropicalis C. parapsilosis Other St. Louis % 13% 17% 7% 1%

3 CANDIDEMIA Species St. Louis CDC NEMIS CDC C. albicans 63% 52% 48% 45% C. glabrata 13% 12% 24% 24% C. tropicalis 17% 10% 19% 12% C. parapsilosis 7% 21% 7% 13% Other 1% 7% 2% 6% CANDIDEMIA Species Frequency (%) Fluconazole MIC Resistance (%) C. albicans C. parapsilosis C. tropicalis C. glabrata C. krusei SENTRY Study, ,047 bloodstream isolates Pfaller et al. J Clin Microbiol 2002;40:

4 CANDIDEMIA: ATTRIBUTABLE MORTALITY Retrospective case-control study matched pairs Crude mortality: 61% of cases 12% of controls Attributable mortality: 49% (38-60% CI) Gudlaugsson O. et al. CID 37(9):1172-7, 2003 IDSA GUIDELINES FOR TREATMENT OF CANDIDIASIS Remove all existing central catheters Medical therapy CID 2004;38: IDSA GUIDELINES FOR TREATMENT OF CANDIDIASIS Remove all existing central catheters Medical therapy: Echinocandin: Caspofungin Azole: Fluconazole Amphotericin B preparation, or Combination therapy fluconazole plus amphotericin B CID 2004;38:161-89

5 CONTROLLED CANDIDEMIA STUDIES: AZOLES STUDY Design Endpoint Success Rate Mortality Rex, 1994 Flu v AmB Up to 12 week 70% v 79% 33% v 40% Rex, 2003 Flu v AmB _ Flu Up to 12 week 56% v 69% 39% v 40% Tuil, 2003 Flu v Itra 12 week F/U 41% v 35% 40% Vori, 2004 Vori v AmB_Flu 12 week F/U Up to 12 week 41% v 41% 65% v 71% 36% v 42% CONTROLLED CANDIDEMIA STUDIES: ECHINOCANDINS STUDY Design Endpoint Success Rate Mortality Mora- Duarte, 2002 Caspo v AmB End of IV Rx 73% v 62% 30% v 34% 2006 Pappas, 2007 Anidulofungin v Flu Mica v Caspo End of Rx End of IV Rx 76% v 30% 71% v 63% 23% v 33% 31% v 26% IDSA GUIDELINES FOR TREATMENT OF CANDIDIASIS Choice depends on: Clinical status Species and susceptibility Relative drug toxicity Prior exposure to antifungals CID 2004;38:161-89

6 IDSA GUIDELINES FOR TREATMENT OF CANDIDIASIS Remove all existing central catheters Medical therapy Retinal examination Treatment duration: 14 days after last positive blood culture and resolution of signs and symptoms CID 2004;38: IMPACT OF IDSA GUIDELINES Prospective study 119 pts at tertiary care hospital Initial antifungal therapy per guidelines 76% Patel et al. Diagnostic Microbiology & Infectious Disease. 52(1):29-34, 2005 IMPACT OF IDSA GUIDELINES Mortality with guidelines: Follow guidelines: 24% Not follow guidelines: 57% (p=0.003) Mortality with ID Consultation: ID Consultation: 18% No ID Consultation: 39% (p<0.01) Patel et al. Diagnostic Microbiology & Infectious Disease. 52(1):29-34, 2005

7 ASPERGILLUS Common mold found in environment Infection due to inhalation of airborne organisms Risk factors: Severe immunocompromise Hematologic malignancy Pulmonary disease Environmental conditions (construction) Consequences of Inhalation of Aspergillus Conidia CONIDIAL ENTRY Mild Chronic Invasion Normal Host Colonization Compromised host No Sequela Preexisting lung cavity Allergy/ Asthma Severe Acute Invasion Aspergilloma Hypersensitivity Conditions Invasive Aspergillosis: Site of Infection in 595 patients Skin 5% Tracheobronchitis 1% Other 9% Multiorgan dissemination 19% Pulmonary 55% Paranasal sinuses 5% CNS 6% Patterson et al, Medicine, 2000;79:

8 CHALLENGE OF INVASIVE ASPERGILLOSIS Invasive aspergillosis (IA) may lead to death within days of first signs of infection Early therapy may decrease mortality Retrospective review: 595 pts with IA: 19% had disseminated disease at time of diagnosis 100 Invasive Aspergillosis Mortality Review of Literature after 1995 Review of 1941 Patients from 50 Studies Case Fatality Rate (%) Overall (1941) BMT (285) Leuk/Lymph (288) Pulm (1153) CNS/Dissem (175) Lin S-J et al, Clin Infect Dis 2001; 32: INVASIVE ASPERGILLOSIS: Disease Spectrum, and Outcome Underlying Disease (n) Complete/Partial Responses (%) Overall (595) 37% Severe Immunosuppression (363) 28 Allo BMT (151) 13 Hematological Malignancy (212) 39 Less Severe Immunosuppression (232) 51 Site of Infection Pulmonary (330) 40% Disseminated (without CNS) (114) 18 Central Nervous System (34) 9 Patterson TF, et al. Medicine, 2000;79:250-60

9 Aspergillosis and Candidiasis in AML Patients Analysis of data from 3012 patients with AML from 18 centers in Italy from 1999 to 2003 Incidence, n (%) (7.1) Aspergillosis Attributable mortality 37.5% (80/213) 124 (4.1) Candidiasis Attributable mortality 35.5% (44/124) AML indicates acute myelogenous leukemia. Pagano L, et al. Haematologica. 2006;91: DIAGNOSTIC CHALLENGES IN ASPERGILLOSIS Variable and non-specific clinical presentation No single, universally applicable test available to establish diagnosis Gold standard: biopsy with evidence of tissue invasion Waiting for definitive diagnosis risks potentially fatal progression of disease Non-Culture Based Diagnosis of Invasive Aspergillosis Culture Biopsy, bronchial washings, sputum Blood (limited utility) CT scan: halo or air crescent signs Product detected Galactomannan EIA Sensitivity lower in non-neutropenic pts False positive results (pip/tazo) Metabolites/other antigens 1,3- β-d-glucan/factor G Walsh et al. CID 2008;46:327-60

10 ASPERGILLOSIS: CURRENT THERAPIES Primary: Voriconazole Alternate: Liposomal AMB (3-5 mg/kg/d) ABLC (5 mg/kg/d) Caspofungin or micafungin Posaconazole Itraconazole Walsh et al. CID 2008;46: Invasive Mycoses: Present and Future Epidemiology Increasing number of patients at risk Changing patterns of disease Major cause of morbidity and mortality Improved prognosis Prompt diagnosis Host factors Antifungal therapy Early, aggressive induction antifungal therapy New approaches and new agents needed THANK YOU